The goal of this project is to understand the actions of a common but poorly understood group of environmental contaminants, the polybrominated diphenyl ethers (PBDEs) and polychlorinated diphenyl ethers (PCDEs) as endocrine disrupters. These compounds are structurally similar to PCB/PBBs, which have known estrogen, anti- estrogenic and thyroid disrupting effects in vertebrates making them strong candidates for endocrine disruptive properties. Their rapidly increasing concentrations in human and wildlife, in conjunction with their embryotoxic effects, raise considerable concerns about their potential harmful effects. Our HYPOTHESIS is that PCDE and PBDEs contribute significantly to the endocrine disrupting potential of environmental contaminants and cause disruption of both reproduction and development in humans and wildlife. This proposal focuses not only on a scarcely studied, but potentially dangerous group of compounds (PBDEs and PCDEs), but is also unique in its multi-species and multi-variate approach, including: a) in vitro tests of species-specific isoforms of estrogen receptor (ER); b) multiple in vivo endpoints (uterotropism, vitellogenin, steroid and thyroid hormones, P450 enzymes); c) multi- generation effects and d) chemical interaction studies on mixtures. In addition to mice, amphibians and fish are located in these studies because they provide especially sensitive and versatile models for endocrine and developmental disruption and are particularly relevant for modeling environmental effects in wildlife. Our synthetic capabilities (Core B) allow us to study a broad range of specific congeners free of trace dibenzofuran contaminants that confounded the results of many earlier studies using commercially available preparation. This research will lead to a better mechanistic understanding of the organs, species and developmental stages most at risk from polyhalogenated diphenyl ethers. In addition, these studies will significantly improve risk assessment strategies by providing multi-species data on structure/activity relationships for PCDE and PBDEs as endocrine disrupters, thereby improving our predictive capabilities for this widespread class of chemical contaminants.